Abstract
BackgroundGenome-wide association studies of Alzheimer’s disease (AD) have implicated pathways related to lipid homeostasis and innate immunity in AD pathophysiology. However, the exact cellular and chemical mediators of neuroinflammation in AD remain poorly understood. The oxysterol 25-hydroxycholesterol (25-HC) is an important immunomodulator produced by peripheral macrophages with wide-ranging effects on cell signaling and innate immunity. Cholesterol 25-hydroxylase (CH25H), the enzyme responsible for 25-HC production, has also been found to be one of the disease-associated microglial (DAM) genes that are upregulated in the brain of AD and AD transgenic mouse models.MethodsWe used real-time PCR and immunoblotting to examine CH25H expression in human AD brain tissue and in transgenic mouse brain tissue-bearing amyloid-β plaques or tau pathology. The innate immune response of primary mouse microglia under different treatment conditions or bearing different genetic backgrounds was analyzed using ELISA, western blotting, or immunocytochemistry.ResultsWe found that CH25H expression is upregulated in human AD brain tissue and in transgenic mouse brain tissue-bearing amyloid-β plaques or tau pathology. Treatment with the toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) markedly upregulates CH25H expression in the mouse brain and stimulates CH25H expression and 25-HC secretion in mouse primary microglia. We found that LPS-induced microglial production of the pro-inflammatory cytokine IL-1β is markedly potentiated by 25-HC and attenuated by the deletion of CH25H. Microglia expressing apolipoprotein E4 (apoE4), a genetic risk factor for AD, produce greater amounts of 25-HC than apoE3-expressing microglia following treatment with LPS. Remarkably, 25-HC treatment results in a greater level of IL-1β secretion in LPS-activated apoE4-expressing microglia than in apoE2- or apoE3-expressing microglia. Blocking potassium efflux or inhibiting caspase-1 prevents 25-HC-potentiated IL-1β release in apoE4-expressing microglia, indicating the involvement of caspase-1 inflammasome activity.Conclusion25-HC may function as a microglial-secreted inflammatory mediator in the brain, promoting IL-1β-mediated neuroinflammation in an apoE isoform-dependent manner (E4>>E2/E3) and thus may be an important mediator of neuroinflammation in AD.
Highlights
Neuroinflammation is a prominent feature of the neuropathology of Alzheimer’s disease (AD), in addition to β-amyloid (Aβ) plaques, tau-containing neurofibrillary tangles (NFT), and synaptic dysfunction followed by neurodegeneration [1]
Cholesterol 25-hydroxylase (CH25H) is upregulated in human AD brain and AD-related transgenic mouse brain We first examined the expression of CH25H in postmortem human AD brain tissue
When we measured CH25H mRNA levels in the frontal cortex of P301S tau transgenic mice that are homozygous for human APOE2 (TE2), APOE3 (TE3), apolipoprotein E4 (APOE4) (TE4) or with no expression of apoe (TEKO) using nanostring analysis, we found that TE4 mice, an aggressive mouse model showing the strongest brain neurodegeneration and neuroinflammation [43], express significantly higher levels of CH25H mRNA than TEKO mice (Fig. 1 g)
Summary
Neuroinflammation is a prominent feature of the neuropathology of Alzheimer’s disease (AD), in addition to β-amyloid (Aβ) plaques, tau-containing neurofibrillary tangles (NFT), and synaptic dysfunction followed by neurodegeneration [1]. Emerging evidence indicates that neuroinflammation, mediated by activated glial cells, plays a fundamental role in the pathogenesis and neurodegeneration of AD [1]. In AD, neuroinflammation increases with disease progression and is primarily driven by glial cells, especially microglia. This pathophysiological inflammatory cascade is associated with increased production of proinflammatory cytokines and other key inflammatory mediators [3, 4], including interleukin-1β (IL-1β), a very potent pro-inflammatory cytokine [5,6,7,8]. Understanding the cellular mechanisms responsible for IL-1β production by microglia may facilitate the development of a disease-modifying AD therapeutic that reduces IL-1β-mediated immune signaling and associated neuroinflammation. Cholesterol 25-hydroxylase (CH25H), the enzyme responsible for 25-HC production, has been found to be one of the disease-associated microglial (DAM) genes that are upregulated in the brain of AD and AD transgenic mouse models
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